The present invention relates generally to medical devices for use in assessing reduced oxygen delivery to regional tissue beds. Specifically, the invention relates to devices and methods for measuring tissue oxygenation either alone or in combination with other parameters such as pH, by using optical reflectance spectrum of the tissue.
Tissue levels of oxygen are an important indicator of the metabolic status of cells. If tissue oxygen falls below cellular demands, then cells perish. Organs, particularly those with high metabolic rates, are especially susceptible to incurring irreversible damage when oxygen is inadequate. It has previously been shown that tissue pH is a useful indicator of anaerobic metabolism, and as such can indicate cells at risk. However, tissue oxygen levels change prior to a drop in pH, so that detection of a low oxygen level could provide an earlier indication of a potential problem. Measurement of tissue oxygenation could also provide a useful early measure to assess the degree of success in restoring oxygen to oxygen-deficient tissue.
Cellular processes are complex, and beyond the question of whether oxygen is transported to the cells in sufficient quantity, one may ask whether the cells are able to use the available oxygen. The combination of a tissue pH measurement and a tissue oxygen measurement would be useful in determining whether a given tissue bed can actually utilize oxygen which is delivered. In a recent paper, applicant has shown that the simultaneous measurement of tissue pH and oxygenation can be used to indicate the onset of dysoxia (defined as the mismatch between oxygen demand and supply). Soller et al., xe2x80x9cApplication of fiberoptic sensors for the study of hepatic dysoxia in swine hemorrhagic shock,xe2x80x9d Crit. Care Med, 29:1438-1444 (2001). The detection of the onset of dysoxia in this manner may therefore permit earlier or more effective preventive interventions in humans. However, the technology for measuring these parameters is at present limited.
Solving this need would be a major contribution to clinical practice. Clinically, oxygen levels can change as a result of many causes: bleeding, trauma, poor cardiac performance, low blood pressure and impaired circulation, among others. Diabetic patients often have compromised tissue perfusion, particularly in their legs and feet. This may result in ulcers and ultimately require amputation. For management of such a chronic condition, it would be especially desirable to possess a technique or sensor for dependably monitoring tissue oxygenation.
Tissue oxygenation is traditionally determined through the measurement of the partial pressure of oxygen (PO2) present in the cells or the interstitial fluid. Typically, tissue PO2 is measured by inserting an invasive PO2 sensor (such as an electrode-based sensor or a dye-coated fiber optic sensor) into the tissue that is to be monitored.
Ideally, it would be advantageous if this measurement could be made spectroscopically, such that the measurement process is non-invasive and does not physically penetrate or stress the tissue. A number of researchers have investigated spectroscopic methods to determine tissue oxygenation. In doing so, they have typically relied upon quantifying some related parameter. For example, some researchers have considered the spectroscopic measurement of arterial or venous blood oxygen to constitute a suitable measure of tissue oxygenation. Arterial blood levels do not, however, respond rapidly to regional changes in reduced oxygen, so this indicator may fail to reflect prevailing tissue oxygenation at a site of interest. Local or regional measurement of venous oxygen saturation, on the other hand, is a satisfactory measure of tissue oxygenation, since local venous blood is collected blood returning from the local tissue. Hutchinson Technology of Hutchinson, Minn. has an existing product which measures venous hemoglobin oxygen saturation in tissue, such as muscle tissues, at depths up to several inches using near infrared (NIR) light. The technology is described, for example, in U.S. Pat. No. 5,879,294 and possibly other patents, and also in promotional material or research publications of that group. Another company, Somonetics, sells a NIR device which measures a combination of venous and arterial oxygen saturation in the brain. A large number of issued patents are also directed to various optical methods of measuring blood and tissue levels of oxygenated hemoglobin or oxygen saturation. These include, for example, U.S. Pat. Nos. 5,515,864, 5,593,899, 5,931,799, 6,015,969, 6,123,597, and 6,216,021. Dr. Britton Chance at the University of Pennsylvania has also patented a number of inventions in this area.
In general, known devices and methods for evaluating the level of oxygen have tended to rely on secondary or related measurements, or upon relatively invasive sensors or slower assays.
It would therefore be desirable to have a system that determines tissue PO2 directly and non-invasively in a local tissue region.
A device in accordance with one aspect of the invention determines the oxygen partial pressure (PO2) of a tissue, which may, for example, be disposed underneath a covering tissue, such as skin, of a patient, or which may be directly contacted or imaged by the device. The device includes a light source for irradiating the tissue with optical radiation such that the light is reflected from the tissue, and also includes a probe for collecting the reflected light to form a reflection spectrum. The device further includes a spectral processor that determines the PO2 level in tissue by processing this spectrum and a mathematical model relating optical properties to PO2 of the tissue.
A method of the invention includes the step of first illuminating the tissue with optical radiation to irradiate the underlying tissue, and collecting a reflection spectrum from the illuminated tissue. The method also includes the step of determining tissue PO2 by processing the collected spectrum with a mathematical model relating optical properties to PO2 of the tissue.
The invention also includes a spectral calibration model for tissue PO2. The model is constructed from a previously compiled calibration data set comprised of direct PO2 measurements and a set of spectral samples collected in coordination with the measurements.
By xe2x80x9ctissuexe2x80x9d, as used herein, is meant any tissue or organ present, e.g., in a patient. This definition encompasses any collection of cells, e.g., epithelial cells, muscle cells, skin cells, or any specific organ, e.g., the heart, kidney, or liver, in the patient. The optical radiation preferably is visible and near infrared radiation or includes a substantial range of near infrared radiation. The radiation may be between about 400 and about 2500 nm, and preferably, the radiation is between 450 and 1100 nm.
The mathematical model of the invention is constructed prior to processing a collected spectrum by first compiling a calibration data set. The calibration data set is formed by collecting multiple optical spectra from a representative tissue sample of a subject, and also measuring the tissue PO2 value simultaneously (e.g., by conventional means). Preferably such data sets are collected from multiple subjects and over a wide range of PO2 values. The optical spectra and known PO2 values are then processed with a mathematical multivariate calibration algorithm, such as a partial least-squares (PLS) fitting algorithm described below, to determine a model, e.g. a formula or calibration equation, relating PO2 to the spectral values collected from the sample. In constructing the model, other parameters, such as pH, temperature and the like may also be measured and fitted to the model, and these subject pH, temperature or other parameters may also be measured at run time for enhanced accuracy. In another embodiment, one or more parameters such as pH, temperature or the like may be varied during acquisition of the calibration data set, serving to enhance the variety of conditions covered by the model, and hence, its accuracy, without becoming explicit variables in the calibration formula so produced.
Once determined, the model is stored, e.g., in the memory of a computer, and then used to transform the optical spectrum obtained from a patient into a PO2 value for the underlying sample tissue. Most preferably, the model used in the analysis step is determined once and is applicable to a wide variety of patients. In this case, the model is preferably robust enough to account for features such as skin color, fat content, weight, etc., which vary from one patient to the next. Alternatively, a range of models can be generated. In this case, during a procedure, the model suitable for a particular patient is selected and is then used to determine the tissue PO2 from spectra acquired from that patient. In yet a different embodiment, a special calibration formula may developed to correct for a specific spectral contribution (e.g., the contribution of skin scattering and coloration in spectra from individuals of diverse ethnicity), and this special calibration formula may be used to pre-process or normalize the spectrum obtained from a given patient prior to applying the PO2 calibration equation. Suitable procedures for effecting such spectral correction are described in commonly-owned U.S. patent application Ser. no. 10/086,917, filed on Feb. 28, 2002, and which is hereby incorporated by reference in its entirety.
The calibration model is a synthetic construct, and is previously and independently constructed by a procedure of first collecting a calibration set comprising a plurality of reflected or transmitted light samples from tissue, and also a plurality of direct PO2 reference measurements from the same tissue, where the light samples and reference measurements are taken in an extended data collection protocol during which the tissue PO2 and other conditions vary over a wide range. The calibration model is then constructed from the calibration set, and is subsequently applied to the spectrum collected from the local region in the tissue of interest. In this manner, tissue PO2, which itself has no xe2x80x9cspectrumxe2x80x9d, is accurately and quickly detected by processing light non-invasively collected at the surface of the local region of tissue.
It is known that a related parameter (e.g., venous oxygen saturation) may be spectrally measured, for example, by the methods reported by Cingo et al. in Proc SPIE, 3911:230-236, (2000) or by Soller et al. in Shock, 15:106-111, (2001), or other known assay, and that venous oxygen saturation is linearly related to tissue PO2 in the range between about 15% and about 80% saturation. Since a number of spectrally significant contributors to oxygenated and deoxygenated hemoglobin, as measured by venous oxygen saturation, are present in the tissue and contribute to the tissue spectrum, the present invention has discovered that by applying a multivariate fitting algorithm to local PO2 measurements and local tissue spectra, it might be possible to develop a xe2x80x9cvirtual modelxe2x80x9d of PO2. During the initial calibration model development, the reference PO2 measurements, may, for example, be taken by an invasive tissue PO2 sensor placed directly in the target tissue or organ. Similarly, the spectrum may be collected from the same tissue site. The model so developed will then accurately represent PO2 itself, rather than a few closely related but potentially divergent factors.
The set of spectral and direct measurements for defining the calibration model are preferably collected as the PO2 level (and other parameters) are varied over an extended range. In a proof-of principle example to construct a calibration equation or model for spectral measurement of tissue PO2, tissue reflectance spectra and raw data measurements are taken every thirty seconds from the muscle of a patient""s palm as the patient undergoes a cardiopulmonary bypass (CPB) procedure. The CPB procedure introduces great changes in pH, mean arterial blood pressure and PO2 over the course of more than an hour for each subject, before the patient""s heart is stopped, the subject is placed on the heart-lung machine and cooled, and the subject is subsequently re-warmed and revived. Data is preferably collected from diabetic and non-diabetic patients, to introduce further range or additional variation in the tissue response data.
The resulting data set with multiple embedded parameter variations is then processed to develop a calibration model for determining tissue PO2 from the collected reflectance spectra returned from the underlying muscle. This model, that is to be later applied to independently-collected spectra from arbitrary subjects, is determined prior to taking a run time reflectance or transmittance spectrum by collecting multiple optical spectra, each occurring at known PO2 values, from a representative sample. The optical spectra and known PO2 values are then processed with a mathematical multivariate calibration algorithm, such as a partial least-squares (PLS) fitting algorithm, to derive the calibration model. The model may feature a linear or non-linear mathematical equation relating actual level of PO2 to a reflection or absorption spectrum taken from the sample. Once constructed or verified, the model is applied to independently-gathered spectra to quantify tissue PO2 directly, non-invasively and in real time.
Thus, the invention provides an optical method for determining the oxygen partial pressure in a tissue. The target tissue may, for example, be disposed underneath a covering tissue (for example, muscle tissue illuminated through the overlying skin), or may be directly accessed by the optical probe (for example, cardiac tissue having an exposed surface and accessed during open chest or minimally-invasive surgery by a fiber optic surface contact probe, or by a focused illuminator/collector probe).